1,4-benzodiazepinones and their uses as CCK antagonists

Abstract

Benzodiazepine derivatives of the formula: wherein R 1 is heterocyclic(lower)alkyl which may have one or more suitable substituent(s), etc., R 2 is lower alkyl, etc., R 3 is indolyl, etc., R 4 is hydrogen, etc., or a pharmaceutically acceptable salt thereof, which are useful as a medicament.

1 . A Compound of the formula:  
       
         
           
           
               
               
           
         
         Wherein  
         R 1  is 
 (1) lower alkyl;  
 (2) hydroxy(lower)alkyl;  
 (3) protected hydroxy(lower)alkyl;  
 (4) heterocyclic(lower)alkyl which may have one or more suitable substituent(s);  
 (5) aryl(lower)alkyl which may have one or more suitable substituent(s);  
 (6) carboxy(lower)alkyl;  
 (7) protected carboxy(lower)alkyl; or  
 (8)  
                     [wherein    A is lower alkylene and    R 5  is 
 (a) lower alkyl,  
 (b) C 3 -C 8  cycloalkyl,  
 (c) adamantyl,  
 (d) aryl which may have one or more suitable substituent(s),  
 (e) amino which may have one or two suitable substituent(s),  
 (f) azabicyclo[3.2.2]nonyl, or  
 (g) saturated heteromonocyclic group containing at least one nitrogen atom, which may have one or more suitable substituent(s)],  
   
 
         R 2  is 
 (1) lower alkyl,  
 (2) C 3 -C 8  cycloalkyl,  
 (3) lower alkoxy(lower)alkyl,  
 (4) C 3 -C 8  cycloalkyl(lower)alkyl,  
 (5) N, N-di(lower)alkylamino(lower)alkyl,  
 (6) lower alkylpiperazinyl(lower)alkyl,  
 (7) lower alkylthio(lower)alkyl,  
 (8) hydroxy(lower)alkyl,  
 (9) protected hydroxy(lower)alkyl,  
 (10)azabicyclo[3.2.2]nonyl(lower)alkyl,  
 (11) aryl which may have one or more suitable substituent(s),  
 (12) cyano,  
 (13) lower alkanoyl,  
 (14) carboxy(lower)alkenyl, or  
 (15) protected carboxy(lower)alkenyl,  
 
         R 3  is indolyl or —NH—R 6  [wherein R 6  is 
 (1) aryl which may have one or more suitable substituent(s),  
 (2) pyridyl which may have one or more suitable substituent(s), or  
 (3)C 3 -C 8  cycloalkyl], and  
 
         R 4  is 
 (1) hydrogen,  
 (2) lower alkyl,  
 (3) halogen, or  
 (4) di(lower)alkylamino,  
 
         with proviso that when R 4  is hydrogen, then R 2  is lower alkyl or C 3 -C 8  cycloalkyl(lower)alkyl,  
         or a pharmaceutically acceptable salt thereof.  
       
     
     
         2 . A Compound of  claim 1 , 
 wherein    R′ is 
 (1) lower alkyl;  
 (2) hydroxy(lower)alkyl;  
 (3) acyloxy(lower)alkyl;  
 (4) heterocyclic(lower)alkyl which may have one or more substituent(s) selected from the group consisting of lower alkyl and acyl;  
 (5) aryl(lower)alkyl which may have one or more acyl(s);  
 (6) carboxy(lower)alkyl;  
 (7) esterified carboxy(lower)alkyl; or  
 (8)  
                     [wherein 
 A is lower alkylene and  
 R 5  is 
 (a) lower alkyl,  
 (b) C 3 -C 8  cycloalkyl,  
 (c) adamantyl,  
 (d) acyl which may have one or more substituent(s)  
 (e) selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, carboxy(lower)alkoxy, protected carboxy(lower)alkoxy, nitro, amino and diacylamino,  
 (e) amino which may have one or two substituent(s) selected from the group consisting of lower alkyl, hydroxy(lower)alkyl, aryl(lower)alkyl and pyridyl,  
 (f) azabicyclo[3.2.2]nonyl, or  
 (g) saturated heteromonocyclic group containing at least one nitrogen atom, which may have one or more substituent(s) selected from the group consisting of carbamoyl, acyl, hydroxy, oxo, aryl, aryl(lower)alkyl, lower alkyl, hydroxy(lower)alkyl, di(lower)alkylcarbamoyl, heterocyclic group, and heterocycliccarbonyl(lower)alkyl],  
 
   
   R 2  is 
 (1) lower alkyl,  
 (2) C 3 -C 8  cycloalkyl,  
 (3) lower alkoxy(lower)alkyl,  
 (4) C 3 -CS cycloalkyl(lower)alkyl,  
 (5) N,N-di(lower)alkylamino(lower)alkyl,  
 (6) lower alkylpiperazinyl(lower)alkyl,  
 (7) lower alkylthio(lower)alkyl,  
 (8) hydroxy(lower)alkyl,  
 (9) acyloxy(lower)alkyl,  
 (10)azabicyclo[3.2.2]nonyl(lower)alkyl,  
 (11) aryl which may have one or more halogen(s),  
 (12) cyano,  
 (13) lower alkanoyl,  
 (14) carboxy(lower)alkenyl, or  
 (15) esterified carboxy(lower)alkenyl,  
   R 3  is indolyl or —NH—R 6  [wherein R 6  is 
 (1) aryl which may have one or more substituent(s) selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, lower alkylthio, hydroxy(lower)alkyl, acyl, halogen, carboxy, protected carboxy, tetrazolyl, triphenyl(lower)alkyltetrazolyl, hydroxyimino(lower)alkyl, sulfo(lower)alkyl, tetrazolyl(lower)alkyl and di(lower)alkylamino,  
 (2) pyridyl which may have one or more lower alkyl(s), or  
 (3) C 3 -C 8  cycloalkyl],  
   R 4  is 
 (1) hydrogen,  
 (2) lower alkyl,  
 (3) halogen or  
 (4) di(lower)alkylamino,  
   with proviso that when R 4  is hydrogen, then R 2  is lower alkyl or C 3 -C 5  cycloalkyl(lower)alkyl,    or a pharmaceutically acceptable salt thereof.    
     
     
         3 . A compound of  claim 1 , 
 wherein    R′ is 
 (1) lower alkyl;  
 (2) hydroxy(lower)alkyl;  
 (3) lower alkanoyloxy(lower)alkyl;  
 (4) heterocyclic(lower)alkyl which may have one or more substituent(s) selected from the group consisting of lower alkyl and lower alkanoyl;  
 (5) aryl(lower)alkyl which may have one or more lower alkanoyl(s);  
 (6) carboxy(lower)alkyl;  
 (7) lower alkoxycarbonyl(lower)alkyl; or  
 (8)  
                     [wherein 
 A is lower alkylene and  
 R 5  is  
 (a) lower alkyl,  
 (b) C 3 -Cl cycloalkyl,  
 (c) adamantyl,  
 (d) aryl which may have one or more substituent(s) selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, carboxy(lower)alkoxy, lower alkoxycarbonyl(lower)alkoxy, nitro, amino and di(lower alkanoyl)amino,  
 (e) amino which may have one or two substituent(s) selected from the group consisting of lower alkyl, hydroxy(lower)alkyl, phenyl(lower)alkyl and pyridyl,  
 (f) azabicyclo[3.2.2]nonyl, or  
 (g) saturated heteromonocyclic group containing at least one nitrogen atom, which may have one or more substituent(s) selected from the group consisting of carbamoyl, lower alkanoyl, hydroxy, oxo, phenyl, phenyl(lower)alkyl, lower alkyl, hydroxy(lower)alkyl, di(lower)alkylcarbamoyl, piperidyl, pyridyl, pyrimidinyl and pyrrolidinylcarbonyl(lower)alkyl,  
   R 2  is 
 (1) lower alkyl,  
 (2) C 3 -C 8  cycloalkyl,  
 (3) lower alkoxy(lower)alkyl,  
 (4) C 3 -C 8  cycloalkyl(lower)alkyl,  
 (5) N,N-di(lower)alkylamino(lower)alkyl,  
 (6) lower alkylpiperazinyl(lower)alkyl,  
 (7) lower alkylthio(lower)alkyl,  
 (8) hydroxy(lower)alkyl,  
 (9) lower alkanoyloxy(lower)alkyl,  
 (10) azabicyclo[3.2.2]nonyl(lower)alkyl,  
 (11) aryl which may have one or more halogen(s),  
 (12) cyano,  
 (13) lower alkanoyl,  
 (14) carboxy(lower)alkenyl, or  
 (15) lower alkoxycarbonyl(lower)alkenyl,  
   R 3  is indolyl or —NH—R 6  [wherein R 6  is 
 (1)aryl which may have one or more substituent(s) selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, lower alkylthio, hydroxy(lower)alkyl, lower alkanoyl, halogen, carboxy, esterified carboxy, tetrazolyl, triphenyl(lower)alkyltetrazolyl, hydroxyimino(lower)alkyl, sulfo(lower)alkyl, tetrazolyl(lower)alkyl, and di(lower)alkylamido,  
 (2) pyridyl which may have one or more lower alkyl(s), or  
 (3) C 3 -C 8  cycloalkyl],  
   R 4  is 
 (1) hydrogen,  
 (2) lower alkyl,  
 (3) halogen or  
 (4) di(lower)alkylamino,  
   with proviso that when R 4  is hydrogen, then R 2  is lower alkyl or C 3 -C 8  cycloalkyl(lower)alkyl,    or a pharmaceutically acceptable salt thereof.    
   
     
     
         4 . A compound of  claim 1 , 
 wherein R 1  is 
 (1) methyl,  
 (2) hydroxyethyl,  
 (3) acetoxyethyl,  
 (4) pyridylmethyl, imidazolylmethyl or thienylmethyl, each of which may have one or more substituent(s) selected from the group consisting of methyl and acetyl,  
 (5) benzyl which may have one or more substituent(s) selected from the group consisting of acetyl,  
 (6) carboxymethyl,  
 (7) ethoxycarbonylmethyl or t-butoxycarbonylmethyl, or  
 (8)  
                     [wherein 
 A is methylene, and  
 R 5  is  
 (a) methyl, ethyl or t-butyl,  
 (b) cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl,  
 (c) adamantyl,  
 (d) phenyl which may have one or more substituent(s) selected from the group consisting of methyl, hydroxy, methoxy, carboxymethoxy, ethoxycarbonylmethoxy, nitro, amino and diacetylamino,  
 (e) amino which may have one or two substituent(s) selected from the group consisting of methyl, ethyl, t-butyl, isopropyl, hydroxyethyl, isobutyl, 1-methyl-1-phenylethyl and pyridyl,  
 (f) azabicyclo[3.2.2]nonyl, or  
 (g) pyrrolidinyl, piperidyl, azacycloheptyl, azacyclooctyl, piperazinyl or morpholinyl, each of which may have one or more substituent(s) selected from the group consisting of carbamoyl, acetyl, hydroxy, oxo, phenyl, benzyl, methyl, hydroxymethyl, hydroxyethyl, diethylcarbamoyl, piperidyl, pyridyl, pyrimidinyl and pyrrolidinylcarbonylmethyl],  
   
 R 2  is 
 (1) methyl, ethyl, isopropyl, isobutyl, butyl or isopentyl,  
 (2) cyclopropyl or cyclohexyl,  
 (3) methoxymethyl,  
 (4) cyclohexylmethyl,  
 (5) N,N-dimethylaminomethyl,  
 (6) methylpiperazinylmethyl,  
 (7) methylthiomethyl,  
 (8) hydroxymethyl,  
 (9) acetoxymethyl,  
 (10) (3-azabicyclo[3.2.2]non-3-yl)methyl,  
 (11) phenyl which may have one or more fluorine(s),  
 (12) cyano,  
 (13) formyl,  
 (14) carboxyvinyl, or  
 (15) ethoxycarbonylvinyl,  
 
 R 3  is indolyl or —NH—R 6  [wherein R 6  is 
 (1) phenyl which may have one or more substituent(s) selected from the group consisting of methyl, hydroxy, methoxy, methylthio, hydroxymethyl, formyl, acetyl, chlorine, bromine, carboxy, t-butoxycarbonyl, tetrazolyl, triphenylmethyltetrazolyl, hydroxyiminomethyl, hydroxyiminoethyl, sulfoethyl, tetrazolylmethyl and N,N-dimethylamino,  
 (2) pyridyl which may have one or more methyl(s), or  
 (3) cyclohexyl],  
 
 R 4  is 
 (1) hydrogen,  
 (2) methyl, ethyl or isopropyl,  
 (3) chlorine, or  
 (4) N,N-dimethylamino,  
 
 with proviso that when R 4  is hydrogen, then R 2  is isopropyl, isobutyl, methyl, isopentyl, ethyl, butyl or cyclohexylmethyl,  
 or a pharmaceutically acceptable salt thereof.  
   
     
     
         5 . A compound of  claim 1 , which is a compound of the formula:  
       
         
           
           
               
               
           
         
         wherein R 2  is lower alkyl or C 3 -C 8  cycloalkyl,  
         R 4  is lower alkyl,  
         R 5  is C 3 -Cl cycloalkyl,  
         R 6  is lower alkylphenyl and  
         A is lower alkylene,  
         or a pharmaceutically acceptable salt thereof.  
       
     
     
         6 . A compound of  claim 1 , which is a compound of the formula:  
       
         
           
           
               
               
           
         
         wherein R 2  is lower alkyl or C 3 -C 8  cycloalkyl,  
         R 4  is lower alkyl,  
         R 5  is C 3 -C 8  cycloalkyl,  
         R 6  is lower alkylphenyl and  
         A is lower alkylene,  
         or a pharmaceutically acceptable salt thereof.  
       
     
     
         7 . A process for preparing a compound of the formula;  
       
         
           
           
               
               
           
         
         Wherein  
         R′ is 
 (1) lower alkyl;  
 (2) hydroxy(lower)alkyl;  
 (3) protected hydroxy(lower)alkyl;  
 (4) heterocyclic(lower)alkyl which may have one or more suitable substituent(s);  
 (5) aryl(lower)alkyl which may have one or more suitable substituent(s);  
 (6) carboxy(lower)alkyl;  
 (7) protected carboxy(lower)alkyl; or  
 (8)  
                     [wherein    A is lower alkylene and    R 5  is 
 (a) lower alkyl,  
 (b) C 3 -C 8  cycloalkyl,  
 (c) adamantyl,  
 (d) aryl which may have one or more suitable substituent(s),  
 (e) amino which may have one or two suitable substituent(s),  
 (f) azabicyclo[3.2.2]nonyl, or  
 (g) saturated heteromonocyclic group containing at least one nitrogen atom, which may have one or more suitable substituent(s)],  
   
 
         R 2  is 
 (1) lower alkyl,  
 (2) C 3 -C 8  cycloalkyl,  
 (3) lower alkoxy(lower)alkyl,  
 (4) C 3 -C 8  cycloalkyl(lower)alkyl,  
 (5) N, N-di(lower)alkylamino(lower)alkyl,  
 (δ) lower alkylpiperazinyl(lower)alkyl,  
 (7) lower alkylthio(lower)alkyl,  
 (8) hydroxy(lower)alkyl,  
 (9) protected hydroxy(lower)alkyl,  
 (10) azabicyclo[3.2.2]nonyl(lower)alkyl,  
 (11) aryl which may have one or more suitable substituent(s),  
 (12) cyano,  
 (13) lower alkanoyl,  
 (14) carboxy(lower)alkenyl, or  
 (15) esterified carboxy(lower)alkenyl,  
 
         R 3  is indolyl or —NH—R 6  [wherein R 6  is 
 (1) aryl which may have one or more suitable substituent(s),  
 (2) pyridyl which may have one or more suitable substituent(s), or  
 (3)C 3 -C 8  cycloalkyl], and  
 
         R 4  is 
 (1) hydrogen,  
 (2) lower alkyl,  
 (3) halogen, or  
 (4) di(lower)alkylamino,  
 
         with proviso that when R 4  is hydrogen, then R 2  is lower alkyl or C 3 -C 8  cycloalkyl(lower)alkyl,  
         or a salt thereof,  
         which comprises,  
         (1) reacting a compound of the formula (II):  
         
           
             
             
                 
                 
             
           
         
         wherein R 1 , R 2  and R 4  are each as defined above, or its reactive derivatives at the amino group or a salt thereof with a compound of the formula (III):  
         
           
             
             
                 
                 
             
           
         
         wherein R 3  is each as defined above, or its reactive derivative or a salt thereof to give a compound of the formula (I):  
         
           
             
             
                 
                 
             
           
         
         wherein R 1 , R 2 , R 3  and R 4  are each as defined above, or a salt thereof,  
         (2) reacting a compound of the formula (IV):  
         
           
             
             
                 
                 
             
           
         
         wherein R 2 , R 3 , and R 4  are each as defined above, or a salt thereof with a compound of the formula (V):  
         X—R′  (V)  
         wherein R 1  is as defined above, X is halogen,or a salt thereof to give a compound of the formula (I):  
         
           
             
             
                 
                 
             
           
         
         wherein R 1 , R 2 , R 3  and R 4  are each as defined above, or a salt thereof,  
         (3) reacting a compound of the formula (VI):  
         
           
             
             
                 
                 
             
           
         
         wherein R 2 , R′, R 4  and A are each as defined above, or its reactive derivative at the carboxy group or a salt thereof with a compound of the formula (VII):  
         
           
             
             
                 
                 
             
           
         
         wherein  
         
           
             
             
                 
                 
             
           
         
         is saturated heteromonocyclic group containing at least one nitrogen atom, which may have one or more suitable substituent(s) or its reactive derivative at the imino group or salt thereof to give a compound of the formula (Ia):  
         
           
             
             
                 
                 
             
           
         
         wherein R 2 , R3, R′, A and  
         
           
             
             
                 
                 
             
           
         
         are each as defined above, or a salt thereof, or  
         (4) reacting a compound of the formula (VI):  
         
           
             
             
                 
                 
             
           
         
         wherein R 2 , R 3 , R 4  and A are each as defined above, or its reactive derivative at the carboxy group or a salt thereof with a compound of the formula (VIII):  
         
           
             
             
                 
                 
             
           
         
         wherein R 7  is hydrogen, lower alkyl, or  
         hydroxy(lower)alkyl, R 8  is lower alkyl,  
         hydroxy(lower)alkyl, aryl(lower)alkyl or pyridyl, or its reactive derivative at the imino group or a salt thereof to give a compound of the formula (Ib):  
         
           
             
             
                 
                 
             
           
         
         wherein R 2 , R 3 , R 4 , R 7 , R 8  and A are each as defined above, or a salt thereof.  
       
     
     
         8 . A pharmaceutical composition which comprises, as an active ingredient, a compound of  claim 1  or a pharmaceutically acceptable salt thereof in admixture with pharmaceutically acceptable carriers.  
     
     
         9 . A use of compound of  claim 1  or a pharmaceutically acceptable salt thereof as a cholecystokinin antagonist.  
     
     
         10 . A method for treating or preventing cholecystokinin-mediated diseases which comprises administering a compound of  claim 1  or a pharmaceutically acceptable salt thereof to human or animals.  
     
     
         11 . A process for preparing a pharmaceutical composition which comprises admixing a compound of  claim 1  or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier.